An understanding of the pathways of immunologic tolerance and the mechanisms of its breakdown in autoimmunity are critical to developing future therapies for a variety of autoimmune disorders, such as diabetes and multiple sclerosis. Novel approaches need to be developed for the treatment of the autoimmune disorders that lead to immune target cell destruction. This Keystone meeting is centered at understanding tolerance and its breakdown and bridging the gap between basic, pre-clinical and clinical studies (the co-chairs have devoted their entire careers to understanding immune tolerance and autoimmunity, including novel therapies). Thus, several speakers (and workshop chairs) will be strongly oriented towards basic studies, while others will focus on diabetes, multiple sclerosis, inflammatory bowel disease, uveitis, and lupus. A major theme will be the underlying tolerance pathways, as well as how they are subverted. Finally, sessions will be devoted to new models and therapies, and a special clinical trials session will be added. A novel feature is the presentation of Lifetime Achievement Awards at the banquet to Drs. Ray Owen and Hugh McDevitt. Sessions (tentative) to be covered include development of the tolerance and lymphoid homeostasis, genetics of autoimmunity, immune suppression, model systems and new therapies for autoimmune diseases, with an emphasis on proof of principle and biotechnology, and clinical trial results. The goals of the meeting are: To provide an understanding of the mechanisms of immune tolerance and its breakdown;To update the audience on autoimmune models and clinical trials; andTo stimulate interactions between basic and clinical scientists, as well as R & D scientists in industry, from around the globe to collaborate to respond to the challenges in this area.